Significance There is a growing need for insulin-sensitizing therapies to treat type 2 diabetes (T2D). In obese T2D humans, NLRP3 inflammasome activation contributes to insulin resistance. Serum levels of retinol binding protein 4 (RBP4) are elevated in obese, insulin-resistant humans and RBP4 SNPs that increase adipose RBP4 expression confer greater T2D risk. RBP4 levels correlate with many metabolic syndrome-related components, including cardiovascular disease. RBP4 elevation induces insulin resistance in mice by increasing proinflammatory cytokine secretion from macrophages. Reducing RBP4 in mice with dietary obesity decreases adipose inflammation and improves insulin sensitivity. Here we show RBP4 primes the NLRP3 inflammasome which plays a critical role in RBP4-induced insulin resistance. Thus, the NLRP3-RBP4 axis may provide therapeutic strategies for T2D and its comorbidities.